Project Summary - Research in the lymphatic circulation is exciting and rich in challenges as its importance in immune cell trafficl<ing, cancer metastasis, and lipid metabolism are quicl<ly becoming more appreciated and as its active roles in such processes are only now being discovered. Because of the complexity of this system, there is great need for new and quantitative tools and models to be developed, and to use those new tools to explore these active roles in interdisciplinary manners. This proposal addresses the active role of lymphatics in lipid transport and metabolism, a topic which is very poorly understood and for which very few tools exist to study It. We will address these issues through three specific aims: 1) Identify and quantify the role of key receptors and proteins involved in the transcytosis of lipid across lymphatic endothelial cells using our previously developed tissue engineered model of the lacteal;2) develop and characterize an in vivo model of lymphatic uptake of lipid by mesenteric lymphatics and use this model to assess the consequences of globally impaired lymphatic function (in knock-out mice) on lipid uptake by lymphatics;3) determine the effects of hyperiipidemia on lymphatic function (particularly the function of the intrinsic lymphatic pump) using a combination of in vitro, in vivo, and isolated vessel models. Collectively these three aims will investigate the balance of lipid and lymphatic function and provide new insight into the resulting consequences of lymphatic or lipid dysfunction on lipid homeostasis and tissue fluid balance.